Insulin is an important glucose-regulating protein. Insulin is a naturally-occurring polypeptide hormone secreted by the pancreas. Insulin is required by the cells of the body to remove and use glucose from the blood. Glucose allows the cells to produce the energy needed to carry out cellular functions. In addition to being the primary effector in carbohydrate homeostasis, it has effects on fat metabolism. It can change the liver's ability to release fat stores. Insulin has various pharmacodynamic effects throughout the body. In healthy individuals, in response to a glucose injection, insulin is rapidly secreted reaching an initial peak within 5-7 minutes and lasting no more than 10-15 minutes (first-phase), followed by a sustained secretion lasting hours (second-phase), see FIG. 1. In Type 2 diabetes, patients experience a loss of first-phase insulin release, despite the enhancement of second-phase insulin secretion. Human data support a critical role for first-phase insulin secretion in postprandial glucose homeostasis (PPG), and evidence supports that increased incidence of cardiovascular disease is associated with PPG.
Researchers first gave an active extract of the pancreas containing insulin to a young diabetic patient in 1922, and the FDA first approved insulin in 1939. The first recombinant human insulin was approved by the FDA in 1982. Recombinant human insulin, insulin lispro, insulin aspart, and insulin glargine are the commonly-used insulins. Beef and pork insulin are infrequently used.
Insulin is used medically when treating some forms of diabetes mellitus. Patients with diabetes mellitus have an inability to take up and use glucose from the blood, and, as a result, the glucose level in the blood rises. In type 1 diabetes, the pancreas cannot produce enough insulin. Therefore, insulin therapy is needed. In type 2 diabetes, patients produce insulin, but cells throughout the body do not respond normally to the insulin. Nevertheless, administration of insulin may also be used in the treatment of type 2 diabetes in order to overcome cellular resistance to insulin. By increasing the uptake of glucose by cells and reducing the concentration of glucose in the blood, insulin prevents or reduces the long-term complications of diabetes, including, for example, damage to the blood vessels, eyes, kidneys, and nerves. Insulin is usually administered by injection under the skin (subcutaneously). The subcutaneous tissue of the abdomen is preferred because absorption of the insulin is more consistent from this location than subcutaneous tissues in other locations.
Insulin can be injected manually, or can be infused into the body with the help of a small electronic infusion device called an insulin pump. Syringes are probably the most common and cost-effective choice for insulin injection, and are useful for patients who take two types of insulin mixed together. An alternative to syringes is an insulin pen, which comes prefilled with insulin and may either be disposable or reusable (with disposable insulin cartridges). The device resembles a large pen, with a fine needle under the cap and a plunger at the other end. A dial allows the user to regulate the dose. Insulin pens are also available in the most frequently-prescribed mixtures of insulin types, such as 70/30 (NPH and regular insulin).
Another device known as an insulin jet injector works by using a high-pressure blast of air to send a fine spray of insulin through the skin. This may be a good option for those patients that are needle-shy. However, jet injectors require a significant financial investment and are not always covered by insurance.
An insulin pump may be a more effective way to control type 1 diabetes for some people because it more closely mimics the insulin production of a pancreas. An insulin pump is a compact electronic device with an attached infusion set (or tube) that administers a small, steady flow of insulin to a patient throughout the day, known as a “basal rate.” Before eating, a pump user programs the pump to deliver a “bolus” of fast-acting insulin to cover the corresponding rise in blood glucose levels from the meal. Pump flow can also be manually adjusted by a user throughout the day as needed.
Disadvantages to patient administration of insulin by injection include discomfort due to multiple daily injections, reaction and infection at the injection site, variation in absorption of subcutaneous insulin, and difficulty in simulating the fast release of endogenous insulin at meal times. Thus, there is a need to develop modes of administration of insulin other than by injection.
When insulin was first discovered and made available for people with diabetes there was only one kind of short-acting insulin. This required several injections a day. As time went on, new insulins were developed that lasted longer, requiring fewer injections, but requiring strict attention to timing of meals. Presently, there are different types of insulin available. This gives more flexibility in the number and timing of administration, making it easier to maintain target blood glucose levels based on a patient's lifestyle. Insulin is available in various forms, for example, rapid-, medium-, and long-acting. Insulin is typically delivered by SC injections. However, other options such as pump delivery, and more recently pulmonary delivery are available. A dry powder formulation of a rapid acting insulin has been described for lung delivery that comprises a human crystalline zinc insulin having the amino acid sequence of natural human insulin (U.S. Pat. No. 6,737,045).
Regular human insulin (e.g., Novolin R, Humulin R) is available in vials, cartridges, and prefilled syringes. Regular human insulin is a molecule known to form molecular complexes via non-covalent interactions (i.e., dimers and hexamers).
Several insulin analogs that are prepared with recombinant DNA technology are available for clinical use. Among these agents is insulin aspart (NovoLog™; Novo Nordisk Pharmaceuticals), which is homologous with regular human insulin except for a single substitution of aspartic acid for proline at position B28. This single substitution reduces the molecule's tendency to form hexamers. Therefore, insulin aspart is absorbed more rapidly after subcutaneous injection and has both a faster onset of action and a shorter duration of action than short-acting insulins.
Insulin mixtures are also used, especially for people with type 2 diabetes. Insulin mixtures allow treatment with different types of insulins in one combined administration.
NPH human insulin (Novolin N, Humulin N) is available in vials, cartridges and prefilled syringes. A mixture of 70% NPH human insulin and 30% regular human insulin (Novolin 70/30, Humulin 70/30) is available in vials, cartridges and pre-filled syringes.
A mixture of 50% NPH human insulin and 50% regular human insulin (Humulin 50/50) is available in vials. Lente human insulin (Novolin L, Humulin L) is available in vials. Ultralente human insulin (Humulin U) is available in vials. Insulin lispro (Humalog) is available in vials and cartridges. Insulin aspart (NovoLog) is available in vials and cartridges. Insulin glargine (Lantus) is available in vials and cartridges.
Insulin is stabilized in the monomeric state to create a rapid-acting form of insulin. When the insulin is stabilized in the hexameric form the time to pharmacodynamic effect (i.e., glucose reduction) is dramatically increased, as compared to monomeric insulin, because the insulin molecules must disassociate before producing the desired biological effect. The injectable insulin treatments that are characterized as rapid acting are chemically modified to maintain the monomer, thereby imparting the rapid pharmacodynamic activity upon injection. Monomeric forms of insulin include insulin analogs and are known to be rapid acting, e.g., insulin glulisine (LysB3, GluB29), HMR-1153 (LysB3, IleB28), HMR-1423 (GlyA21, HisB31, HisB32), insulin aspart (AspB28) or (AspB10), and lispro (LysB28, ProB29). In every instance above, the nomenclature of the analogs is based on a description of the amino acid substitution at specific positions on the A or B chain of insulin, numbered from the N-terminus of the chain, in which the remainder of the sequence is that of natural human insulin.
There is a need to develop pharmaceutical formulations comprising ultra-rapid acting insulin, i.e., insulin which are able to provide peak serum levels in less than 60 minutes and glucose troughs in less than 90 minutes.